Overall and complete response rates as potential surrogates for overall survival in relapsed/refractory multiple myeloma.

Aim: The correlation between response and survival has not been well-studied in relapsed or refractory multiple myeloma (RRMM). Materials & methods: A systematic literature review of Medline, Embase and Cochrane databases (2010-06/2020) and relevant congresses (2018-2020) was performed to identify randomized clinical trials in RRMM reporting median overall survival (mOS), progression-free survival and response end points. The relationship between mOS and response end points was analyzed using Pearson's product-moment correlation. Results: A total of 81 records for 65 original studies, representing 12,827 patients were included. The correlation was moderate for mOS with overall response rate (Pearson r = 0.79), very good partial response (r = 0.73) and duration of response (r = 0.78); all were statistically significant. In linear regression models, estimated mOS gain was 0.48, 0.47 and 1.94 months per percentage point of overall response rate, very good partial response and complete response, respectively (all p < 0.001). Significance was maintained after adjustment for age, relapsed versus refractory multiple myeloma and study year. The analysis was limited by small sample sizes and inconsistent reporting of study-level covariates. Conclusion: These findings support short-term response-based end points as surrogates to survival in RRMM.

Treatments for multiple myeloma may not work for every patient and the cancer may come back. In clinical trials, it is difficult to find out how well new treatments work in allowing patients to live longer. This is especially true when patients have advanced disease that has returned or has not responded to treatment. How well a patient responds to treatment (i.e., has a decreased extent of disease) could indicate whether the drug will help the patient live longer, but the relationship between response to treatment and survival is not fully understood. We conducted a systematic review and meta-analysis to better understand how response rates and survival are related. A systematic review collects all the published research on a specific subject, and a meta-analysis is a statistical method that creates a single finding from several separate studies. This study found a moderate relationship between how long patients live after receiving treatment for multiple myeloma and their response to treatment. This would allow response-to-treatment data from clinical trials to be used to predict better survival and show the drug can help patients.

Real-world evidence in lung and hematologic oncology health technology appraisals: a review of six assessment agencies.

Aim: To assess the use and acceptability of real-world evidence (RWE) in lung and hematologic cancer appraisals. Materials & methods: A review of appraisals published by National Institute for Health and Care Excellence (NICE) in the UK was conducted. A total of 20 case studies employing RWE were identified and compared across five additional health technology assessment agencies: Scottish Medicines Consortium (SMC) (Scotland), CADTH (Canada), INESSS (Quebec), HAS (France) and IQWiG (Germany). Results: Of 80 RWE references from 20 case studies from NICE, 67 were identified in the respective CADTH submissions, 46 in IQWiG, 37 in INESSS, 37 in HAS, and 33 in SMC. NICE had the highest RWE acceptance rate (90%), followed by HAS (88%), SMC (82%), INESSS (73%), IQWiG (68%) and CADTH (67%). Conclusion: RWE was generally accepted by respective committees, allowing improved access to innovative treatments.

Use of real-world evidence for assessing the value of cancer treatments Health technology assessment (HTA) is a process used to decide whether a drug works well enough to be worth paying for. Most drugs have data showing how well they work from special studies called clinical trials. Sometimes a manufacturer also has evidence of a drug or disease that is not from a clinical trial but from the real world. This review discusses how real-world evidence (RWE) is being used for HTAs of new lung and blood cancer therapies. We reviewed twenty HTA submissions for new therapies. All twenty were submitted to these agencies: National Institute for HealthCare and Excellence (NICE; UK), Scottish Medicines Consortium (SMC; Scotland), Canadian Agency for Drugs and Technologies in Health (CADTH; Canada), National Institute of Excellence in Health and Social Services (INESSS; Quebec), French National Authority for Health (HAS; France) and Institute for Quality and Efficiency in HealthCare (IQWiG; Germany). RWE was often used to describe the type of patient that needs the new therapy. RWE was also used to show the cost of the treatment and how well the treatment worked in relation to its cost. It was also used to show how well the new therapy works compared with other treatments. Most of the RWE was accepted by the agencies. High-quality RWE in relevant patients helped support access to new treatments.

Epidemiology, Healthcare Resource Utilization, and Mortality of Asthma and COPD in COVID-19: A Systematic Literature Review and Meta-Analyses.

Purpose: There has been concern that asthma and chronic obstructive pulmonary disease [COPD] increase the risk of developing and exacerbating COVID-19. The effect of medications such as inhaled corticosteroids (ICS) and biologics on COVID-19 is unclear. This systematic literature review analyzed the published evidence on epidemiology and the burden of illness of asthma and COPD, and the use of baseline medicines among COVID-19 populations. Patients and Methods: Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, Embase®, MEDLINE® and Cochrane were searched (January 2019-August 2021). The prevalence of asthma or COPD among COVID-19 populations was compared to the country-specific populations. Odds ratios (ORs) were estimated to compare healthcare resource utilization (HCRU) rates, and meta-analyses of outcomes were estimated from age-adjusted ORs (aORs) or hazard ratios (aHRs). Meta-analyses of COVID-19 outcomes were conducted using random effects models for binary outcomes. Results: Given the number and heterogeneity of studies, only 183 high-quality studies were analyzed, which reported hospitalization, intensive care unit (ICU) admissions, ventilation/intubation, or mortality. Asthma patients were not at increased risk for COVID-19-related hospitalization (OR = 1.05, 95% CI: 0.92 to 1.20), ICU admission (OR = 1.21, 95% CI: 0.99 to 1.1.48), ventilation/intubation (OR = 1.24, 95% CI: 0.95 to 1.62), or mortality (OR = 0.85, 95% CI: 0.75 to 0.96). Accounting for confounding variables, COPD patients were at higher risk of hospitalization (aOR = 1.45, 95% CI: 1.30 to 1.61), ICU admission (aOR = 1.28, 95% CI: 1.08 to 1.51), and mortality (aOR = 1.41, 95% CI: 1.37 to 1.65). Sixty-five studies reported outcomes associated with ICS or biologic use. There was limited evidence that ICS or biologics significantly impacted the risk of SARS-CoV-2 infection, HCRU, or mortality in asthma or COPD patients. Conclusion: In high-quality studies included, patients with asthma were not at significantly higher odds for adverse COVID-19-related outcomes, while patients with COPD were at higher odds. There was no clear evidence that baseline medication affected outcomes. Registration: PROSPERO (CRD42021233963).

Non-small cell lung cancer with EGFR exon 20 insertion mutation: a systematic literature review and meta-analysis of patient outcomes.

INTRODUCTION: EGFR exon 20 insertion mutation-positive non-small cell lung cancer (NSCLC) is rare, has a poor prognosis, and outcomes are not fully established. We describe and evaluate outcomes from real-world and clinical evidence in these patients. METHODS: A systematic literature review (SLR) identified interventional and real-world evidence (RWE) studies reporting clinical outcomes for EGFR exon 20 insertion mutation-positive NSCLC. Meta-analyses were conducted by line of therapy to synthesize pooled survival and response outcomes across RWE. Published evidence from interventional studies was summarized individually. RESULTS: The SLR identified 23 RWE and 19 original interventional studies. In the meta-analysis of RWE, pooled response and survival outcomes were low for first-line EGFR-tyrosine kinase inhibitors (TKIs) and immuno-oncology (IO) agents. First-line chemotherapy resulted in a pooled ORR 25.7%, pooled PFS 5.6 months, and pooled OS 18.3 months. Pooled outcomes were further reduced in second or later lines (≥2 L): pooled ORR was 5.0%, 3.3%, and 13.9%; pooled PFS was 2.1 months, 2.3 months, and 4.4 months; and pooled OS was 14.1 months, 8.8 months, and 17.1 months (not a pooled result) for EGFR-TKIs, IO agents, and chemotherapy, respectively. Interventional studies reported outcomes for TKIs (mobocertinib, poziotinib, osimertinib, afatinib, CLN-081, DZD9008), a monoclonal antibody (amivantamab), and a heat shock protein 90 inhibitor (luminespib). While there is limited RWE for the recently approved agents mobocertinib and amivantamab, which specifically target exon 20 insertion mutations, interventional evidence supports their potential as effective treatment options. CONCLUSIONS: Conventional treatments used in patients with EGFR exon 20 insertion mutation-positive NSCLC have limited efficacy, though chemotherapy appeared to be associated with better response and survival outcomes than non-exon 20 targeting EGFR-TKIs and IO agents. This supports the need to identify EGFR exon 20 insertion mutations as the availability of new targeted treatments may offer additional therapeutic options to these patients.

Response rates and minimal residual disease outcomes as potential surrogates for progression-free survival in newly diagnosed multiple myeloma.

Progression-free survival (PFS) is a common primary endpoint in newly diagnosed multiple myeloma (NDMM). Patients with NDMM typically have longer PFS and are more likely to achieve minimal residual disease (MRD) or complete response (CR) compared to patients with relapsed or refractory multiple myeloma. Response-based surrogate endpoints may hold value given the longer follow-up time required to evaluate PFS in NDMM. In this work, systematic literature reviews of Medline, Embase, and Cochrane databases (2010-06/2020) and relevant congresses (2018-2020) were performed to identify randomized clinical trials (RCTs) and real-world studies in NDMM reporting median PFS and objective response. Associations between PFS and each response endpoint were evaluated using Pearson's product-moment correlation weighted by sample size in each RCT arm. Unadjusted and adjusted weighted linear regression models were applied to estimate the gain in median PFS associated with each response endpoint. Statistically significant correlations were identified for median PFS with overall response rate (ORR; Pearson r = 0.59), CR (r = 0.48), stringent CR (sCR; r = 0.68), and MRD (r = 0.69). The unadjusted models estimated 0.50 (95% CI: 0.36, 0.64; p<0.001), 0.42 (95% CI: 0.25, 0.58; p<0.001), 1.05 (95% CI: 0.58, 1.52; p<0.001), and 0.35 (95% CI: 0.12, 0.58; p = 0.006) months of median PFS gained per point of ORR, CR, sCR, and MRD, respectively. Associations for median PFS remained statistically significant in models adjusted for age and treatment type with ORR (0.35, 95% CI: 0.21, 0.49; p<0.001), and adjusted for age and International Staging System risk stage with CR (0.29, 95% CI: 0.16, 0.41; p<0.001). Due to small sample size, adjusted models could not be constructed for sCR or MRD. Nevertheless, evidence of significant survival benefit (p<0.05) associated with MRD negativity and sCR was identified across real-world studies. These findings provide support for the use of response outcomes as surrogate endpoints to estimate PFS benefit in NDMM.

Humanistic and Economic Burden of Conversion Therapy Among LGBTQ Youths in the United States.

IMPORTANCE: Sexual orientation and gender identity change efforts (SOGICE), also called conversion therapy, is a discredited practice attempting to convert lesbian, gay, bisexual, transgender, queer, or questioning (LGBTQ) individuals to be heterosexual and/or cisgender. OBJECTIVES: To identify and synthesize evidence on the humanistic and economic consequences of SOGICE among LGBTQ youths in the US. DESIGN, SETTING, AND PARTICIPANTS: This study, conducted from December 1, 2020, to February 15, 2021, included a systematic literature review and economic evaluation. The literature review analyzed published evidence on SOGICE among LGBTQ individuals of any age. The economic model evaluated the use of SOGICE vs no intervention, affirmative therapy vs no intervention, and affirmative therapy vs SOGICE to estimate the costs and adverse outcomes for each scenario and to assess the overall US economic burden of SOGICE. Published literature and public sources were used to estimate the number of LGBTQ youths exposed to SOGICE, the types of therapy received, and the associated adverse events (anxiety, severe psychological distress, depression, alcohol or substance abuse, suicide attempts, and fatalities). EXPOSURES: SOGICE (licensed or religion-based practitioners) or affirmative therapy (licensed practitioners). MAIN OUTCOMES AND MEASURES: Total incremental costs and quality-adjusted life-years (QALYs) vs no intervention and total economic burden of SOGICE. RESULTS: Among 28 published studies, which included 190 695 LGBTQ individuals, 12% (range, 7%-23%) of youths experienced SOGICE, initiated at a mean age of 25 years (range, 5-58 years), with a mean (SD) duration of 26 (29) months. At least 2 types of SOGICE were administered to 43% of recipients. Relative to LGBTQ individuals who did not undergo SOGICE, recipients experienced serious psychological distress (47% vs 34%), depression (65% vs 27%), substance abuse (67% vs 50%), and attempted suicide (58% vs 39%). In the economic analysis, over a lifetime horizon with a 3% annual discount rate, the base-case model estimated additional $97 985 lifetime costs per individual, with SOGICE associated with 1.61 QALYs lost vs no intervention; affirmative therapy yielded cost savings of $40 329 with 0.93 QALYs gained vs no intervention. With an estimated 508 892 youths at risk for SOGICE in 2021, the total annual cost of SOGICE is estimated at $650.16 million (2021 US dollars), with associated harms totaling an economic burden of $9.23 billion. CONCLUSIONS AND RELEVANCE: This economic evaluation study suggests that there is a high economic burden and high societal costs associated with SOGICE and identifies additional research questions regarding the roles of private and public funding in supporting this harmful practice.

Treatment Outcomes of High-Risk Non-Muscle Invasive Bladder Cancer (HR-NMIBC) in Real-World Evidence (RWE) Studies: Systematic Literature Review (SLR).

BACKGROUND: To date, there has been limited synthesis of RWE studies in high-risk non-muscle invasive bladder cancer (HR-NMIBC). The objective of this research was to conduct a systematic review of published real-world evidence to better understand the real-world burden and treatment patterns in HR-NMIBC. METHODS: An SLR was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines with the scope defined by the Population, Intervention Comparators, Outcomes, and Study design (PICOS) criteria. EMBASE, MEDLINE, and Cochrane databases (Jan 2015-Jul 2020) were searched, and relevant congress abstracts (Jan 2018-Jul 2020) identified. The final analysis only included studies that enrolled ≥100 patients with HR-NMIBC from the US, Europe, Canada, and Australia. RESULTS: The SLR identified 634 RWE publications in NMIBC, of which 160 studies reported data in HR-NMIBC. The average age of patients in the studies was 71 years, and 79% were males. The rates of BCG intravesical instillations ranged from 3% to 86% (29-95% for induction and 8-83% for maintenance treatment). Five-year outcomes were 17-89% recurrence-free survival (longest survival in patients completing BCG maintenance), 58-89% progression-free survival, 71-96% cancer-specific survival (lowest survival in BCG-unresponsive patients), and 28-90% overall survival (lowest survival in patients who did not receive BCG or instillation therapy). CONCLUSION: BCG treatment rates and survival outcomes in patients with HR-NMIBC vary in the real world, with better survival seen in patients completing maintenance BCG, responding to treatment, and not progressing to muscle-invasive disease. There is a need to better understand the factors associated with BCG use and discontinuation and for an effective treatment that improves outcomes in HR-NMIBC. Generalization of these results is limited by variations in data collection, reporting, and methodologies used across RWE studies.

Clinical Burden and Unmet Need in Recurrent Pericarditis: A Systematic Literature Review.

Inflammation of the pericardium (pericarditis) is characterized by excruciating chest pain. This systematic literature review summarizes clinical, humanistic, and economic burdens in acute, especially recurrent, pericarditis, with a secondary aim of understanding United States treatment patterns and outcomes. Short-term clinical burden is well characterized, but long-term data are limited. Some studies report healthcare resource utilization and economic impact; none measure health-related quality-of-life. Pericarditis is associated with infrequent but potentially life-threatening complications, including cardiac tamponade (weighted average: 12.7% across 10 studies), constrictive pericarditis (1.84%; 9 studies), and pericardial effusion (54.7%; 16 studies). There are no approved pericarditis treatments; treatment guidelines, when available, are inconsistent on treatment course or duration. Most recommend first-line use of conventional treatments, for example, nonsteroidal antiinflammatory drugs with or without colchicine; however, 15-30% of patients experience recurrence. Second-line therapy may involve conventional therapies plus long-term utilization of corticosteroids, despite safety issues and the difficulty of tapering or discontinuation. Other exploratory therapies (eg, azathioprine, immunoglobulin, methotrexate, anakinra) present steroid-sparing options, but none are supported by robust clinical evidence, and some present tolerability challenges that may impact adherence. Pericardiectomy is occasionally pursued in treatment-refractory patients, although data are limited. This lack of an evidence-based treatment pathway for patients with recurrent disease is reflected in readmission rates, for example, 12.2% at 30 days in 1 US study. Patients with continued recurrence and inadequate treatment response need approved, safe, accessible treatments to resolve pericarditis symptoms and reduce recurrence risk without excessive treatment burden.

A Systematic Literature Review of the Epidemiology, Health-Related Quality of Life Impact, and Economic Burden of Immunoglobulin A Nephropathy.

Introduction: This systematic literature review analyzed published evidence on IgA nephropathy (IgAN), focusing on US epidemiology, health-related quality of life (HRQoL), and economic burden of illness. Methods: Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, Embase®, MEDLINE®, Cochrane, and Econlit (January 2010 to June 2020) were searched, along with relevant congresses (2017-2020). Results: Of 123 epidemiologic studies selected for data extraction, 24 reported IgAN diagnosis rates ranging from 6.3% to 29.7% among adult and pediatric patients undergoing renal biopsy, with all reported US rates <15%. No US studies reported IgAN prevalence. A meta-analysis of US studies calculated an annual incidence of 1.29/100 000 people, translating to an annual US incidence of 4236 adults and children. Relative to Europe, the United States had more patients diagnosed with IgAN in later chronic kidney disease stages. US rates of transition to end-stage renal disease (ESRD) ranged from 12.5% to 23% during 3-3.9 years of observation, rising to 53% during 19 years of observation. Across 8 studies reporting HRQoL, pain and fatigue were the most reported symptoms, and patients consistently ranked kidney function and mortality as the most important treatment outcomes. Patients with glomerulopathy reported worse mental health than healthy controls or hemodialysis patients; proteinuria was significantly associated with poorer HRQoL and depression. Conclusion: While economic evidence in IgAN remains sparse, management of ESRD is a major cost driver. IgAN is a rare disease where disease progression causes increasing patient burden, underscoring the need for therapies that prevent kidney function decline and HRQoL deterioration while reducing mortality.

What Does the Economic Burden of Acute Myeloid Leukemia Treatment Look Like for the Next Decade? An Analysis of Key Findings, Challenges and Recommendations.

Acute myeloid leukemia (AML) is conventionally treated with chemotherapy in eligible patients. Potentially curative regimens are associated with significant toxicity, and the major cost drivers in AML historically have been hospitalization and hematopoietic stem cell transplantation. The past several years have seen a dramatic increase in the number of treatment options, including oral therapies and drugs targeted to biological pathways implicated in AML. Major current and future drivers of cost in AML include hospitalization and medical costs, stem cell transplantation for eligible patients, and medication costs. It is likely that hospitalization and medical costs will decline as more AML treatment moves to the outpatient setting. Stem cell transplantation costs may increase, if more patients are eligible for improved procedures, although the overall cost of transplantation could decrease if new procedures reduce the need for hospitalization. Medication costs are likely to increase, with various branded drugs available and in development. From a broader perspective, another driver of cost is the proportion of patients with AML who can undergo treatment. Patients who may previously have been unable to tolerate chemotherapy are more likely to be treated with the range of less intensive, more tolerable options now available. The effectiveness of newer AML treatment options also suggests that, overall, there may be more patients staying alive and on treatment longer than in the past. While certain advances, such as increased use of oral and outpatient therapies, could potentially reduce costs, the overall economic impact of AML is likely to increase as more patients are eligible for novel therapies across several phases from induction to maintenance to relapsed/refractory disease. While these novel therapies have the potential to deliver value in the form of improved efficacy, safety, and convenience, payers will need to determine how to cover a longer, more complex AML treatment pathway.

Economic burden of acute steroid-refractory graft-versus-host disease in commercially insured pediatric patients.

BACKGROUND: Acute graft-versus-host disease (aGVHD), a potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT), often occurs within 100 days of HSCT. While steroids are typically used as first-line treatment, there is no consensus on second-line steroid-refractory (SR) treatments. SR aGVHD is associated with significantly worse pediatric health outcomes, but less is known about its economic impact. OBJECTIVE: To evaluate the economic burden of SR pediatric aGVHD in a commercially insured US patient population. METHODS: Retrospective analyses were conducted using medical and pharmacy claims data from the HealthCore Integrated Research Database (study period January 1, 2006-May 31, 2019). Included patients had at least 1 claim for allogeneic HSCT (earliest HSCT claim set as index date), no claims for autologous HSCT, and no pre-index GVHD. Patients were aged less than 18 years with no minimum pre- or post-index continuous enrollment. The GVHD cohort included patients with at least 1 claim for aGVHD over 100 days from index with at least 1 claim for any steroid and at least 1 claim for second-line therapy, both on or after the date of the first aGVHD claim. Patients post-HSCT with no GVHD claims over follow-up formed the comparison cohort. Health care resource utilization and costs over 12 months from the index date were calculated and compared between cohorts using parametric testing. RESULTS: 38 patients with SR aGVHD and 184 controls were included. Mean age and sex were similar for aGVHD (8.6 years, 50% female) and control (8.2 years, 45% female). During the 12-month post-index follow-up, SR aGVHD patients had higher rates of complications vs controls (* for P < 0.05): anemia (79% vs 68%), drug-induced anemia* (53% vs 34%), neutropenia (63% vs 53%), thrombocytopenia (58% vs 42%), gastrointestinal complications* (95% vs 65%), and infections* (95% vs 79%). Mean inpatient length of stay was longer by 31.6 days (P < 0.01) with a total average of 96.0 days for those with SR aGVHD vs 64.3 days for the controls. More SR aGVHD patients required inpatient total parenteral nutrition (71% vs 58%), readmission within 12 months of discharge from index hospitalization* (89% vs 60%), ER visits (34% vs 24%), and outpatient visits (100% vs 86%). Total 12-month mean medical costs were higher in aGVHD patients: $1,212,944 vs $673,491 (P < 0.001), mostly because of complication-related costs: $868,966 vs $396,757 (P < 0.001). Among patients with SR aGVHD, mean total costs were higher by about $1.8 million ($2,609,445 vs $812,385; P = 0.014) for those who died compared with those who were alive within 12 months. CONCLUSIONS: SR aGVHD in pediatric patients following HSCT is associated with incremental 12-month medical costs of greater than $500,000, driven largely by complications. DISCLOSURES: This research was sponsored by Mesoblast, Inc. Grabner is an employee of HealthCore, Inc., which acted as consultants to Mesoblast, Inc., during the conduct of this research. Strati is an employee of Mesoblast, Inc. Sandman and Forsythe are employees of Purple Squirrel Economics, which acted as consultants to Mesoblast, Inc., during the conduct of this research. This work was presented at the AMCP Annual Meeting online in April 2020 and was an encore presentation at AMCP Nexus 2020 Virtual in October 2020.

Comparative Effectiveness of Remestemcel-L-rknd versus Ruxolitinib in Pediatric Patients with Steroid-Refractory Acute Graft-Versus-Host Disease using Simulated Treatment Comparisons.

Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) can be a lifesaving treatment for hematologic malignancies, but acute graft-versus-host-disease (aGVHD) is a potentially deadly adverse effect experienced by up to half of allo-HSCT recipients. Inadequate response to steroid therapy for aGVHD is associated with poor prognosis and high mortality, including among pediatric patients, who are the focus of this study. Ruxolitinib and remestemcel-L-rknd were evaluated for the treatment of steroid-refractory (SR) aGVHD in two separate single-arm trials. To effectively compare the safety and efficacy of these treatments without a head-to-head trial, a simulated treatment comparison (STC) was conducted. Methods: Regression techniques were used to adjust individual patient-level data from the remestemcel-L-rknd trial to mutually reported baseline characteristics from the ruxolitinib trial. Outcomes of interest included a 28-day overall response rate (ORR), a 28-day ORR in the grade III-IV aGVHD population, and adverse events (AEs). Results: In the full populations, the STC of risk ratios (RRs) found treatment with remestemcel-L-rknd to be associated with a numerical but not statistically significant improvement in the 28-day ORR versus ruxolitinib. In the grade III-IV aGVHD sub-group, the STC showed significantly improved 28-day ORR for remestemcel-L-rknd versus ruxolitinib (P=0.04). Remestemcel-L-rknd was also associated with improved safety outcomes (P<0.05) in 17 out of 30 AEs, including hematologic events, peripheral edema, muscular weakness, nausea, back pain, and fatigue. Conclusion: Remestemcel-L-rknd was associated with significant improvements in day 28 ORR compared with ruxolitinib in patients with severe (grade III-IV) SR aGVHD. Across all grades of SR aGVHD, remestemcel-L-rknd was associated with fewer all-grade treatment-emergent adverse events (TEAEs) (27/30) available for comparison, including the majority reaching statistical significance.

Humanistic and Economic Burden of Non-Muscle Invasive Bladder Cancer: Results of Two Systematic Literature Reviews.

PURPOSE: Non-muscle invasive bladder cancer (NMIBC) is a malignancy restricted to the inner lining of the bladder. Intravesical Bacillus Calmette-Guerin (BCG) following transurethral resection of the bladder tumor is the mainstay first-line treatment for high-risk NMIBC patients. Two systematic literature reviews (SLRs) were conducted to further assess the current evidence on BCG use in NMIBC and the humanistic and economic burden of disease. METHODS: Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, Embase® and MEDLINE® were searched using the Ovid platform to identify interventional or real-world evidence studies on the health-related quality of life (HRQoL) and economic burden in NMIBC. Limited evidence was found from initial economic SLR searches in NMIBC, so additional targeted searches for bladder cancer were conducted to expand findings. RESULTS: Fifty-nine publications were included in the HRQoL SLR, of which 23 reported HRQoL and symptoms in NMIBC. At diagnosis, HRQoL was comparable with population norms but worsened considerably 2 years following diagnosis. Maintenance therapy with intravesical BCG was associated with reduced HRQoL, and treatment-related adverse events (AEs) resembled typical NMIBC symptoms. Twenty-two studies reported decreasing BCG compliance over time. Common AEs with BCG were frequent urination, lower urinary tract symptoms, pain, and hematuria. Forty-two publications were included in the economic SLR, of which nine assessed healthcare costs and resource use in NMIBC or bladder cancer. High-risk disease and high-intensity treatment were associated with increased healthcare costs. CONCLUSION: NMIBC has a considerable symptomatic, HRQoL, and economic burden. Symptoms persisted and HRQoL worsened despite intravesical BCG treatment. NMIBC is a costly disease, with higher healthcare costs associated with increased risk of disease progression and recurrence. There is a high unmet need for safe and effective treatments that reduce the risk of disease progression and recurrence, provide symptomatic relief, and improve HRQoL for patients.

Ct Dosimetry for The Australian Cohort Data Linkage Study.

Children undergoing computed tomography (CT) scans have an increased risk of cancer in subsequent years, but it is unclear how much of the excess risk is due to reverse causation bias or confounding, rather than to causal effects of ionising radiation. An examination of the relationship between excess cancer risk and organ dose can help to resolve these uncertainties. Accordingly, we have estimated doses to 33 different organs arising from over 900 000 CT scans between 1985 and 2005 in our previously described cohort of almost 12 million Australians aged 0-19 years. We used a multi-tiered approach, starting with Medicare billing details for government-funded scans. We reconstructed technical parameters from national surveys, clinical protocols, regulator databases and peer-reviewed literature to estimate almost 28 000 000 individual organ doses. Doses were age-dependent and tended to decrease over time due to technological improvements and optimisation.

US database study: burden and healthcare resource utilization in adults with systemic endemic mycoses and aspergillosis.

Aim: This study evaluated burden of illness in immunocompromised patients with systemic mycoses (SM) eligible for itraconazole treatment, specifically, histoplasmosis, blastomycosis and aspergillosis. Methods: A cross-sectional study used an electronic medical record network integrating information from 30 US hospitals, including >34 million patients, to evaluate burden and healthcare resource utilization over 6 months following initiation of antifungal therapy. Results: Symptomatic burden experienced by each of the otherwise healthy or age >65 or immunosuppressed cohorts receiving antifungal therapy for SM was comparable but significantly greater in cancer or HIV patients and transplant recipients. Across groups, there was substantially higher healthcare resource utilization in patients with SM versus matched controls without SM. Conclusion: The total impact of SM is particularly severe in high-risk or vulnerable populations.

The Cost-effectiveness of Eltrombopag for the Treatment of Immune Thrombocytopenia in the United States.

PURPOSE: Eltrombopag was evaluated as a second-line treatment for adult chronic immune thrombocytopenia (ITP) in the 2006 Phase III RAISE (Eltrombopag for Management of Chronic Immune Thrombocytopenia) randomized, placebo-controlled trial. More than 80% of patients reached satisfactory platelet counts within 2 weeks. However, the economic value of eltrombopag as a second-line treatment for ITP remains to be formally assessed. This study aimed to estimate the cost-effectiveness of treating ITP with a comparable thrombopoietin receptor agonist (eltrombopag vs romiplostim). METHODS: A Markov model was implemented over a lifetime time horizon to estimate the benefits and costs of each treatment. The model featured 3 health states based on current guidelines: (1) on treatment; (2) treatment failure/discontinuation; and (3) mortality. In line with therapeutic goals in ITP, model patients could experience 3 events: no bleeding, mild/moderate bleeding, or severe bleeding. Data on eltrombopag use were obtained from an open-label extension of previous Phase II/III trials, including RAISE. Romiplostim data were obtained from Phase III trials and an extension study. Lifetime overall survival was extrapolated by using treatment-specific mortality rates derived from severe bleeding and natural mortality rates. The costs of drugs, routine care, bleeding episodes, adverse events, and mortality were represented in the model. FINDINGS: Eltrombopag-treated patients gained 17.58 life years and 14.68 quality-adjusted life years, whereas romiplostim-treated patients gained 17.52 life years and 14.67 quality-adjusted life years. The total lifetime cost of eltrombopag treatment was estimated at $1.58 million versus $2.13 million for romiplostim. Sensitivity analyses supported base case findings. Deterministic sensitivity analysis predicted the greatest sensitivity to the rates of severe bleeding, discontinuation, and natural mortality. Probabilistic sensitivity analysis showed that eltrombopag would be an efficient use of resources at a $50,000 threshold in 52.8% of cases. In all probabilistic iterations, the total cost of eltrombopag treatment was lower than with romiplostim, primarily because of lower drug costs. IMPLICATIONS: Clinical data were applied in an economic analysis, and eltrombopag exhibited economic dominance compared with romiplostim, driven largely by the reduced costs of primary therapy. This model was limited by a lack of specific patient-level data and robust data on the duration of secondary therapy, as well as by the fact that utilization values are likely conservative estimates for routine care use.

Real-world evidence on clinical outcomes in immune thrombocytopenia treated with thrombopoietin receptor agonists.

Aim: Eltrombopag and romiplostim are US FDA approved for treatment of immune thrombocytopenia in patients with insufficient response to other treatments. Clinical or real-world data comparing outcomes of the two drugs are limited. Methods: This retrospective cross-sectional study sought information on bleeding-related episodes (BREs), adverse events (AEs) and other outcomes of eltrombopag or romiplostim treatment in immune thrombocytopenia. Results: Patients receiving eltrombopag experienced significantly reduced BREs, severe BREs, rescue medication use and platelet transfusions. Diarrhea and headache were significantly less frequent in patients receiving eltrombopag; other AEs occurred equally in both groups. Conclusion: There may be a potential advantage for the use of eltrombopag versus romiplostim in the practice settings studied, based on rates of BREs and AEs and rescue medication utilization.

Cost-effectiveness of midostaurin in the treatment of newly diagnosed FLT3-mutated acute myeloid leukemia in France.

BACKGROUND: Midostaurin (MIDO) combined with standard chemotherapy was approved by the European Medicines Agency in 2017 for the treatment of adults with newly diagnosed FLT3-mutated acute myeloid leukemia (AML) based on results from the RATIFY trial. METHODS: A cost-effectiveness model was developed to compare MIDO and standard-of-care (SOC) to SOC alone in France. Per Haute Autorité de Santé (HAS) guidelines, a partitioned survival model with eight health states was used: diagnosis/induction, complete remission, relapse, hematopoietic stem cell transplantation (HSCT), HSCT recovery, post-HSCT recovery (stabilized after HSCT recovery), post-HSCT relapse, and mortality. A lifetime horizon was used beginning at diagnosis with a "cure model,", which assumed natural mortality after trial cut-off. Utility values were obtained from a systematic literature review and included disutilities. Resource utilization was based on HAS clinical guidelines and a survey of French physicians and included drugs and administration, adverse events, routine medical care, HSCT, and end-of-life care costs. RESULTS: In RATIFY and after extrapolation, MIDO improved survival compared to SOC, translating into MIDO-treated patients gaining 1.12 life years (LYs) and 1.23 quality-adjusted life years (QALYs) versus SOC. The incremental cost-effectiveness ratio (ICER) for MIDO versus SOC was €68,781 per LY and €62,305 per QALY. Sensitivity analyses showed consistency with base case findings. CONCLUSIONS: MIDO represents a clinically significant advancement in the management of newly diagnosed FLT3-mutated AML. In this analysis, MIDO add-on therapy showed gains in LYs and QALYs versus SOC alone and was found to be a cost-effective option at a €100,000 per QALY threshold for end-of-life treatment.

A systematic review and meta-analysis of neurotrophic tyrosine receptor kinase gene fusion frequencies in solid tumors.

INTRODUCTION: The research objective was to systematically review evidence on neurotrophic tyrosine receptor kinase (NTRK) gene fusion frequency in solid tumors. METHODS: Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic literature review (SLR) was conducted of studies published from January 1987 to 2 January 2020. Selected studies were appraised for use in meta-analysis, with frequency reported as a point estimate with confidence intervals, to estimate NTRK gene fusion tumor incidence and prevalence. RESULTS: The SLR identified 222 studies from North America (n = 122), Europe (n = 33), Asia (n = 41), Brazil (n = 5), Australia (n = 2), and multi-continental (n = 19) reporting NTRK gene fusion frequencies across 101 histologies. Studies were prospective (n = 43) and retrospective (n = 179). Testing methods involved DNA (n = 93), RNA (n = 72), combined DNA/RNA (n = 48), protein [immunohistochemistry (IHC), n = 5], and unreported (n = 5). Sample sizes ranged from 1 to 66,871. Of the 222 studies, 107 were suitable for meta-analysis. Highest NTRK gene fusion frequencies were reported in rare cancers: infantile/congenital fibrosarcoma (90.56%, 95% CI 67.42-100.00), secretory breast cancer (92.87%, 95% CI 72.62-100.00), and congenital mesoblastic nephroma (21.52%, 95% CI 13.06-32.20). Lower frequencies were reported in non-small cell lung cancer (0.17%, 95% CI 0.09-0.25), colorectal adenocarcinoma (0.26%, 95% CI 0.15-0.36), cutaneous melanoma (0.31%, 95% CI 0.07-0.55), and non-secretory breast carcinoma (0.60%, 95% CI 0.00-1.50). Reported frequency was ~0% for some cancers: mesothelioma, renal cell carcinoma, prostate cancer, and bone sarcoma. Estimated global overall NTRK gene fusion tumour incidence and 5-year prevalence in 2018 was 0.52 and 1.52 per 100,000 persons, respectively. CONCLUSION: This research confirms the rarity and varying frequency of NTRK gene fusion across tumor types. Limitations included relatively low historic NTRK gene fusion testing and reporting, limited study samples for some cancers, and suboptimal molecular testing methods. In this rapidly developing area, gold-standard testing methods and companion diagnostics are needed to capture all NTRK gene fusions.